CN113717189B - Preparation method of 10-methoxy camptothecine - Google Patents
Preparation method of 10-methoxy camptothecine Download PDFInfo
- Publication number
- CN113717189B CN113717189B CN202111171834.5A CN202111171834A CN113717189B CN 113717189 B CN113717189 B CN 113717189B CN 202111171834 A CN202111171834 A CN 202111171834A CN 113717189 B CN113717189 B CN 113717189B
- Authority
- CN
- China
- Prior art keywords
- camptothecine
- methoxy
- crude product
- product
- hydroxycamptothecin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- KLFJSYOEEYWQMR-NRFANRHFSA-N 10-methoxycamptothecin Chemical compound C1=C(OC)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 KLFJSYOEEYWQMR-NRFANRHFSA-N 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims abstract description 29
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 claims abstract description 26
- 239000012043 crude product Substances 0.000 claims abstract description 23
- HAWSQZCWOQZXHI-UHFFFAOYSA-N CPT-OH Natural products C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 239000000047 product Substances 0.000 claims abstract description 19
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 230000011987 methylation Effects 0.000 claims abstract description 15
- 238000007069 methylation reaction Methods 0.000 claims abstract description 15
- 238000004537 pulping Methods 0.000 claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 9
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229940127093 camptothecin Drugs 0.000 claims abstract description 8
- 238000000746 purification Methods 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 238000001027 hydrothermal synthesis Methods 0.000 claims description 12
- 239000002244 precipitate Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 claims description 9
- 239000012153 distilled water Substances 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 9
- 238000009210 therapy by ultrasound Methods 0.000 claims description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 238000001291 vacuum drying Methods 0.000 claims description 7
- XVMZDZFTCKLZTF-UHFFFAOYSA-N 9-methoxycamtothecin Natural products C1=CC(OC)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 XVMZDZFTCKLZTF-UHFFFAOYSA-N 0.000 claims description 6
- KLFJSYOEEYWQMR-UHFFFAOYSA-N CPT-OMe Natural products C1=C(OC)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 KLFJSYOEEYWQMR-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 238000011935 selective methylation Methods 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 6
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 230000001035 methylating effect Effects 0.000 abstract 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- -1 methyl halide Chemical class 0.000 description 4
- 241000759905 Camptotheca acuminata Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 3
- 239000004810 polytetrafluoroethylene Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- FBDOJYYTMIHHDH-OZBJMMHXSA-N (19S)-19-ethyl-19-hydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-2,4,6,8,10,14,20-heptaen-18-one Chemical compound CC[C@@]1(O)C(=O)OCC2=CN3Cc4cc5ccccc5nc4C3C=C12 FBDOJYYTMIHHDH-OZBJMMHXSA-N 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000012022 methylating agents Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to a preparation method of 10-methoxy camptothecine. Taking 10-hydroxycamptothecin as a raw material, taking dimethyl carbonate as a methylation reagent, selectively methylating to obtain a 10-methoxyl camptothecin crude product, and pulping and purifying to obtain a 10-methoxyl camptothecin product. The selectivity of the reaction is improved by optimizing the solvent consumption, the content of the 10-methoxy camptothecine in the crude product of the 10-methoxy camptothecine can reach 89%, the purity of the target product can reach more than 95% after one-time pulping and purification, the yield can reach more than 80%, the preparation operation is simple, the methylating reagent is nontoxic, the product purification is easy, and the preparation method belongs to a green preparation method.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of 10-methoxy camptothecine.
Background
Camptothecin (CPT) is an alkaloid extracted from specific plant camptotheca acuminata in China by Wall et al in 1966. In early in vitro activity screening, camptothecine shows stronger anti-tumor activity and has obvious inhibition effect on various solid tumors and leukemia. However, camptothecine has poor water solubility and strong toxic and side effects, so that the application of camptothecine in tumor treatment is limited. Hsiang Y.H. in 1985, discovered that camptothecins exert cytotoxic activity by inhibiting topoisomerase I and have attracted attention again. Many researchers have begun to invest in modification and improvement of the chemical structure of camptotheca acuminata and have been devoted to improving their absorption conditions in the human body and enhancing the therapeutic effect. The 10-methoxy camptothecine can be used as a raw material for structural modification of camptothecine medicines.
Chemical structural formula of 10-methoxy camptotheca acuminata alkali
At present, the preparation method of the 10-methoxy camptothecine generally adopts 10-hydroxy camptothecine extracted from plants or takes the 10-hydroxy camptothecine as raw material for methylation synthesis. 10-hydroxycamptothecin is utilized to prepare 10-methoxyl camptothecin, most of the selected methylation reagents are methyl halide and dimethyl sulfate, and the methylation reagents are high in toxicity, inflammable and explosive, and have great environmental pollution and great harm to human bodies; and the purification process of the product requires column chromatography, which is complex in operation.
Disclosure of Invention
The technical problem to be solved by the invention is to provide the preparation method of the 10-methoxy camptothecine, which is simple to operate, high in yield and friendly to the environment.
The technical scheme provided by the invention is as follows:
a preparation method of 10-methoxy camptothecine is characterized in that 10-hydroxy camptothecine is taken as a raw material, dimethyl carbonate is taken as a methylation reagent, 10-methoxy camptothecine crude product is obtained through selective methylation, and 10-methoxy camptothecine product is obtained through pulping and purification; the preparation method comprises the following steps in sequence:
(1) Methylation of 10-hydroxycamptothecin to prepare a 10-methoxyl camptothecin crude product: sequentially adding 10-hydroxycamptothecin, N-dimethylformamide, dimethyl carbonate and cesium carbonate into a hydrothermal reaction kettle, carrying out ultrasonic treatment for 10 minutes, placing the hydrothermal reaction kettle into an oven at 110-150 ℃ for constant-temperature reaction for 8-12 hours, concentrating reaction liquid under reduced pressure after the reaction is finished, dripping concentrated liquid into distilled water under stirring, acidifying with hydrochloric acid until precipitation, filtering and washing the obtained precipitate, and vacuum drying to obtain a 10-methoxyl camptothecin crude product; the dosage of the N, N-dimethylformamide is 10-15 ml/g of 10-hydroxycamptothecin;
(2) Pulping and purifying the crude product of the 10-methoxy camptothecine to obtain a 10-methoxy camptothecine product: and (3) pulping and purifying the 10-methoxy camptothecin crude product obtained in the step (1) by using a dichloromethane-ethyl acetate mixed solvent at room temperature to obtain a 10-methoxy camptothecin product, wherein the volume ratio of the dichloromethane-ethyl acetate mixed solvent to the methanol is 1:1, and the dosage of the dichloromethane-ethyl acetate mixed solvent is 50-100 ml/g of the 10-methoxy camptothecin crude product.
The reaction solution was concentrated under reduced pressure as described in step (1) to recover dimethyl carbonate by distillation under reduced pressure.
The beneficial effects of the invention are as follows:
according to the invention, dimethyl carbonate is used as a methylation reagent, the selectivity of the reaction is improved through optimizing the solvent consumption, the content of 10-methoxyl camptothecine in the crude product of 10-methoxyl camptothecine can reach 89%, the purity of a target product can reach more than 95% after one-time pulping purification, the yield can reach more than 80%, the preparation operation is simple, the methylation reagent is nontoxic, the product purification is easy, and the preparation method belongs to a green preparation method.
Drawings
FIG. 1 is a high performance liquid chromatogram of the product obtained in step (1) of example 1.
FIG. 2 is a high performance liquid chromatogram of the product obtained in example 2.
FIG. 3 is a high performance liquid chromatogram of the product obtained in example 3.
Detailed Description
The invention is described in further detail below with reference to examples:
a preparation method of 10-methoxy camptothecine is characterized in that 10-hydroxy camptothecine is taken as a raw material, dimethyl carbonate is taken as a methylation reagent, 10-methoxy camptothecine crude product is obtained through selective methylation, and 10-methoxy camptothecine product is obtained through pulping and purification; the preparation method comprises the following steps in sequence:
(1) Methylation of 10-hydroxycamptothecin to prepare a 10-methoxyl camptothecin crude product: sequentially adding 10-hydroxycamptothecin, N-dimethylformamide, dimethyl carbonate and cesium carbonate into a hydrothermal reaction kettle, carrying out ultrasonic treatment for 10 minutes, placing the hydrothermal reaction kettle into an oven at 110-150 ℃ for constant-temperature reaction for 8-12 hours, concentrating reaction liquid under reduced pressure after the reaction is finished, dripping concentrated liquid into distilled water under stirring, acidifying with hydrochloric acid until precipitation, filtering and washing the obtained precipitate, and vacuum drying to obtain a 10-methoxyl camptothecin crude product; the dosage of the N, N-dimethylformamide is 10-15 ml/g of 10-hydroxycamptothecin;
(2) Pulping and purifying the crude product of the 10-methoxy camptothecine to obtain a 10-methoxy camptothecine product: and (3) pulping and purifying the 10-methoxycamptothecine crude product obtained in the step (1) by using a dichloromethane-ethyl acetate mixed solvent at room temperature to obtain a 10-methoxycamptothecine product, wherein the volume ratio of dichloromethane to ethyl acetate is 1:1, and the dosage of the dichloromethane-ethyl acetate mixed solvent is 50-100 ml/g of the 10-methoxycamptothecine crude product.
The reaction solution was concentrated under reduced pressure as described in step (1) to recover dimethyl carbonate by distillation under reduced pressure.
The present invention is described in more detail in the following examples, which are not to be construed as limiting the invention.
Example 1
(1) 3.64 g (0.01 mol) of 10-hydroxycamptothecin, 50 ml of N, N-dimethylformamide, 4.54 g (0.05 mol) of dimethyl carbonate and 2 g (0.006 mol) of cesium carbonate are sequentially added into a polytetrafluoroethylene lining of a 100 ml hydrothermal reaction kettle, the kettle cover is screwed up after ultrasonic treatment for 10 minutes (yellow suspension is obtained), the hydrothermal reaction kettle is placed in an oven for reaction at the constant temperature of 140 ℃ for 12 hours, after the reaction is finished, the reaction solution is decompressed and concentrated to recover dimethyl carbonate, the concentrated solution is dripped into 500 ml of distilled water under stirring, the pH value of the solution is adjusted to pH=2 by 3M hydrochloric acid, a large amount of precipitate is precipitated at the moment, the precipitate obtained by suction filtration and washing with 100 ml of distilled water is three times, and 4.4 g of yellow 10-methoxycamptothecine crude product is obtained by vacuum drying. The content of 10-methoxy camptothecine is 89.67% by high performance liquid chromatography (normalization method). In FIG. 1, 11.104 minutes is the peak of 10-hydroxy-20-methoxycamptothecine; 11.671 min was 10-methoxycamptothecine peak; 18.229 min shows a peak for 10-methoxy-20-methoxycamptothecine.
(2) Adding 4 g of 10-methoxy camptothecin crude product into 300 ml of dichloromethane-ethyl acetate mixed solvent with the volume ratio of 1:1, carrying out ultrasonic treatment at room temperature for 15 minutes, standing for 30 minutes, carrying out ultrasonic treatment for 5 minutes, carrying out suction filtration, washing the obtained precipitate with 20 ml of dichloromethane-ethyl acetate mixed solvent with the volume ratio of 1:1 for three times, and carrying out vacuum drying to obtain 3.3 g of pale yellow 10-methoxy camptothecin product. The content of 10-methoxy camptothecine is 95.43% by high performance liquid chromatography (normalization method).
Example 2
0.364 g (0.001 mol) of 10-hydroxycamptothecin, 50 ml of N, N-dimethylformamide, 0.454 g (0.005 mol) of dimethyl carbonate and 0.2 g (0.0006 mol) of cesium carbonate are sequentially added into a polytetrafluoroethylene lining of a 100 ml hydrothermal reaction kettle, the kettle cover is screwed up after ultrasonic treatment for 10 minutes (yellow clear transparent liquid is obtained), the hydrothermal reaction kettle is placed in an oven for constant temperature reaction for 12 hours at 140 ℃, after the reaction is finished, the reaction liquid is dripped into 500 ml of distilled water under stirring, the pH value of the solution is regulated to pH=2 by 3M hydrochloric acid, a large amount of precipitate is precipitated at the moment, the precipitate obtained by suction filtration is washed three times by 100 ml of distilled water, and 0.4 g of earthy yellow powder is obtained by vacuum drying. The content of 10-methoxy camptothecine is not detected by high performance liquid chromatography. In FIG. 2, 11.103 min is the peak of 10-hydroxy-20-methoxycamptothecine and 18.229 min is the peak of 10-methoxy-20-methoxycamptothecine
Example 3
0.364 g (0.001 mol) of 10-hydroxycamptothecin, 5 ml of N, N-dimethylformamide, 0.091 g (0.001 mol) of dimethyl carbonate and 0.2 g (0.0006 mol) of cesium carbonate are sequentially added into a polytetrafluoroethylene lining of a 20 ml hydrothermal reaction kettle, the kettle cover is screwed up after ultrasonic treatment for 10 minutes (yellow suspension), the hydrothermal reaction kettle is placed in an oven for constant temperature reaction for 15 hours at 140 ℃, after the reaction is finished, the reaction solution is dripped into 50 ml of distilled water under stirring, the pH value of the solution is regulated to pH=2 by 3M hydrochloric acid, a large amount of precipitate is precipitated at this time, the obtained precipitate is filtered by suction and washed three times by 10 ml of distilled water, and 0.37 g of earthy yellow powder is obtained by vacuum drying. By high performance liquid chromatography, the content of 10-methoxycamptothecine is not detected, and 10-hydroxycamptothecin base is not reacted. In FIG. 3, 9.364 minutes is the peak of 10-hydroxycamptothecin.
Comparative examples 1, 2 and 3 show that the preparation of 10-methoxycamptothecine using dimethyl carbonate as the methylating agent requires an excess of dimethyl carbonate, which would tend to cause methylation of the 20-hydroxy group of 10-hydroxycamptothecin. Examples 1 and 2 show that selective methylation of the hydroxyl groups at the 10-and 20-positions of 10-hydroxycamptothecin can be achieved by controlling the amount of solvent added (N, N-dimethylformamide is a solvent for 10-hydroxycamptothecin, and cesium carbonate). When the addition amount of the solvent is small (10-15 ml/g of 10-hydroxycamptothecin), the reaction system is high in alkalinity, so that 10-site hydroxyl is changed into oxyanion, the nucleophilicity is improved, and under the condition, 10-site hydroxyl methylation mainly occurs. When the addition amount of the solvent is increased, the alkalinity of the reaction system is reduced, the 10-position hydroxyl group is not favorable to be changed into oxyanion, and the 20-position hydroxyl methylation mainly occurs because the nucleophilicity of the phenolic hydroxyl group is smaller than that of the alcoholic hydroxyl group.
Claims (2)
1. A preparation method of 10-methoxy camptothecine is characterized in that 10-hydroxy camptothecine is taken as a raw material, dimethyl carbonate is taken as a methylation reagent, 10-methoxy camptothecine crude product is obtained through selective methylation, and 10-methoxy camptothecine product is obtained through pulping and purification; the preparation method comprises the following steps in sequence:
(1) Methylation of 10-hydroxycamptothecin to prepare a 10-methoxyl camptothecin crude product: sequentially adding 10-hydroxycamptothecin, N-dimethylformamide, dimethyl carbonate and cesium carbonate into a hydrothermal reaction kettle, carrying out ultrasonic treatment for 10 minutes, placing the hydrothermal reaction kettle into an oven, carrying out constant-temperature reaction for 8-12 hours at 110-150 ℃, concentrating the reaction liquid under reduced pressure after the reaction is finished, dripping the concentrated liquid into distilled water under stirring, acidifying with hydrochloric acid until precipitation is obtained, filtering and washing the obtained precipitate, and carrying out vacuum drying to obtain a 10-methoxycamptothecin crude product; the dosage of the N, N-dimethylformamide is 10-15 ml/g of 10-hydroxycamptothecin; the amount of the substance of dimethyl carbonate is 5 times that of 10-hydroxycamptothecin;
(2) Pulping and purifying the crude product of the 10-methoxy camptothecine to obtain a 10-methoxy camptothecine product: and (3) pulping and purifying the 10-methoxycamptothecine crude product obtained in the step (1) by using a dichloromethane-ethyl acetate mixed solvent at room temperature to obtain a 10-methoxycamptothecine product, wherein the volume ratio of dichloromethane to ethyl acetate is 1:1, and the dosage of the dichloromethane-ethyl acetate mixed solvent is 50-100 ml/g of the 10-methoxycamptothecine crude product.
2. The process according to claim 1, wherein the reaction solution in step (1) is concentrated under reduced pressure to recover dimethyl carbonate by distillation under reduced pressure.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111171834.5A CN113717189B (en) | 2021-10-08 | 2021-10-08 | Preparation method of 10-methoxy camptothecine |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111171834.5A CN113717189B (en) | 2021-10-08 | 2021-10-08 | Preparation method of 10-methoxy camptothecine |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113717189A CN113717189A (en) | 2021-11-30 |
CN113717189B true CN113717189B (en) | 2024-01-26 |
Family
ID=78685666
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111171834.5A Active CN113717189B (en) | 2021-10-08 | 2021-10-08 | Preparation method of 10-methoxy camptothecine |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113717189B (en) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1587265A (en) * | 2004-07-08 | 2005-03-02 | 浙江大学 | 10-alkoxy camptothecine derivative and its preparing method and use |
CN102746315A (en) * | 2011-12-23 | 2012-10-24 | 浙江大学 | Preparation method and use of 10-<11>C-methoxycamptothecin |
CN104370862A (en) * | 2013-08-13 | 2015-02-25 | 中国人民解放军军事医学科学院毒物药物研究所 | Water-soluble antitumor compound |
CN106946674A (en) * | 2017-03-03 | 2017-07-14 | 山东达冠生化科技股份有限公司 | A kind of environmentally friendly P-methoxybenzal-dehyde synthetic method |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102649795B (en) * | 2011-06-23 | 2014-08-06 | 东北林业大学 | 10-methoxyl camptothecin derivative, preparation method and application |
-
2021
- 2021-10-08 CN CN202111171834.5A patent/CN113717189B/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1587265A (en) * | 2004-07-08 | 2005-03-02 | 浙江大学 | 10-alkoxy camptothecine derivative and its preparing method and use |
CN102746315A (en) * | 2011-12-23 | 2012-10-24 | 浙江大学 | Preparation method and use of 10-<11>C-methoxycamptothecin |
CN104370862A (en) * | 2013-08-13 | 2015-02-25 | 中国人民解放军军事医学科学院毒物药物研究所 | Water-soluble antitumor compound |
CN106946674A (en) * | 2017-03-03 | 2017-07-14 | 山东达冠生化科技股份有限公司 | A kind of environmentally friendly P-methoxybenzal-dehyde synthetic method |
Non-Patent Citations (2)
Title |
---|
Synthesis and Anticancer Evaluation of Novel 10-Methoxycamptothecin Derivatives;Meixuan Zhu等;Asian Journal of Chemistry;第27卷(第3期);932-934 * |
Synthesis of new cytotoxic E-ring modified camptothecins;Salvatore Cananzi等;Tetrahedron Letters;第51卷;6489-6492 * |
Also Published As
Publication number | Publication date |
---|---|
CN113717189A (en) | 2021-11-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110407847B (en) | Azaphilones compounds obtained from aspergillus terreus and preparation and application thereof | |
CN112409307B (en) | Compound Olerafuran A in purslane, and extraction and separation method and application thereof | |
CN109836401A (en) | A kind of purification process of docetaxel | |
CN110668967B (en) | Photocatalytic preparation method of alpha-ketoamide compound | |
CN112300104B (en) | Lignanoid compound in purslane and extraction and separation method and application thereof | |
CN113717189B (en) | Preparation method of 10-methoxy camptothecine | |
CN109096347B (en) | Method for purifying high-purity 3,2 ', 6' -tri-N-acetyl gentamicin C1a alkali (P1) | |
US11465971B2 (en) | Method for preparing mesaconine and related intermediaries thereof | |
CN109988127B (en) | Method for synthesizing taxol from 7-differential-10-deacetyltaxol | |
CN109251196B (en) | Aminobenzo [ d ] aza-quinazoline compound and preparation method and application thereof | |
CN101148437B (en) | Biinomenine derivative connected with C-C bond, preparation method and application thereof | |
CN115073406B (en) | Eucalyptus type sesquiterpene lactone TBA derivative and application thereof | |
CN106749098B (en) | A kind of preparation method preparing dioxopromethazine hydrochloride using oxygen as oxidant | |
CN111004145B (en) | Chiral optical amide substituted alpha, beta-diamino acid derivative and preparation method and application thereof | |
CN108125962B (en) | Application of benzo [ d ] aza-quinazoline compound in preparation of drugs for treating lung cancer | |
CA2590756C (en) | Stereoselective process and crystalline forms of a camptothecin | |
CN104334561B (en) | compound JK12A and preparation thereof | |
CN113956266A (en) | Method for synthesizing tetrodotoxin on large scale | |
CN101270119A (en) | Technique for purifying spherosinin from leguminosae pointvetch or milk vetch | |
CN101314587B (en) | Preparation for midbody of Irinotecan and preparation for Irinotecan | |
CN109651413B (en) | Rare earth complex with bromo-oxidized bicuculline as ligand and synthetic method and application thereof | |
CN114773354B (en) | Simple synthesis method of Trisphaeridine | |
CN109456335B (en) | Method for synthesizing oxidized bicuculline | |
CN113999154B (en) | Compound and preparation method and application thereof | |
CN114588155A (en) | Application of centipede quinoline compound |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |